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Synlett 2009(11): 1835-1841  
DOI: 10.1055/s-0029-1217369
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Highly Stereoselective Dimerization of 3-Alkoxyimino-2-aryl-alkylnitriles via Oxidative Carbon-Carbon Bond Formation

Yunfei Du*, Yongliang Zhang, Songqing Wang, Kang Zhao*
Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, P. R. of China
Fax: +86(22)27890968; e-Mail: kangzhao@tju.edu.cn;
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Publication History

Received 16 March 2009
Publication Date:
12 June 2009 (online)

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Abstract

The MnO2-mediated oxidative dimerization of a series of 3-alkoxyimino-2-aryl-alkylnitriles was investigated. The developed method stereospecifically afforded solely the corresponding C2-symmetric dl-dimers, with the trans-configuration of the C=N double bonds, in good to excellent yields under mild conditions. The alkoxyimino substituents in the substrates and a thermodynamically controlled mechanism are proposed to be essential for the stereo­selectivity of this radical dimerization process.

Key words

MnO2 - oxidative dimerization - 3-alkoxyimino-2-aryl-alkylnitriles - dl-dimers - stereoselectivity

    References and Notes

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    An excess of MnO2 (4 equiv) was used for a complete conversion of 1a into dimerized dl-2a within a shorter period of time (1 h) although two equivalents of MnO2 was enough for the total consumption of 1a.

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13

Compound dl-2n: Crystallized in the monoclinic space group P2 (1) with cell dimensions: a = 8.0723 (11) Å, b = 26.531 (4) Å, c = 16.356 (2) Å, α = 90˚, β = 92.325 (2)˚, γ = 90˚, V = 3499.9 (8) ų, Dc = 1.227 g/cm³, Z = 2. CCDC: 712678.

15

General Procedure for the Synthesis of the Homocoupling Dimers dl -2: To a solution of 3-alkoxyimino-2-aryl-alkylnitriles 1 (4 mmol) in CH2Cl2 (30 mL) was added, in one portion, the dried MnO2 (16 mmol) powder with stirring at room temperature. TLC was used to monitor the reaction process until the total consumption of 1 was observed. The insoluble materials were removed via filtration and the filtrate was evaporated in vacuum to remove the solvent. The residue was then purified by flash silica gel chromatography, using a mixture of petroleum ether (PE) and EtOAc as eluent, to afford the desired homodimers 2. The synthesis of 12 (dl + meso) from 11 was conducted under similar reaction conditions.

16

Procedures for the Synthesis of dl -4 and 5: Case 1: When either MnO2 or Ag2O was used as the oxidant, the reactions were conducted following the procedure described for the synthesis of dimers dl-2. Case 2: When K3Fe(CN)6 was used as the oxidant: A mixture of 3 (5 mmol), K3Fe(CN)6 (20 mmol), and aq 10% NaOH (35 mmol) in MeOH (20 mL) was stirred at r.t. for 0.5 h. The reaction mixture was then extracted with EtOAc (3 × 20 mL) and the combined organic layer, after drying over anhydrous Na2SO4, was evaporated to remove the solvent. The residue was purified by silica gel column to give the homodimerized dl-4 in 86% yield, with no separation of 5.

17

General Procedure for the Synthesis of Heterodimerized dl -Dimers: A mixture of dl-2b (0.30 mmol) and dl-2c (0.30 mmol) in toluene (20 mL) was stirred at reflux for 30 min. After cooling to room temperature, the mixture was evaporated to remove the solvent. The residue was passed through silica gel column using a mixture of PE and EtOAc as eluent, to give the heterodimerized dl-9. Unreacted dl-2b and dl-2c were also recovered.

18

Substrates 1a, 1c, 1d, 1f and 1m were synthesized and characterized in our previous work (see reference 11). The others substrates were characterized as follows: (1b) White solid; mp 55-57 ˚C; ¹H NMR (500 MHz, CDCl3): δ(trans) = 7.29-7.18 (m, 4 H), 4.70 (s, 1 H), 3.93 (s, 3 H), 2.36 (s, 3 H), 1.77 (s, 3 H); δ(cis) = 7.29-7.18 (m, 4 H), 5.78 (s, 1 H), 3.93 (s, 3 H), 2.36 (s, 3 H), 1.91 (s, 3 H); HRMS (ESI): m/z [M + H+] calcd for C12H15N2O: 203.1179; found: 203.1180. (1e) White solid; mp 74-75 ˚C; ¹H NMR (500 MHz, CDCl3): δ(trans) = 7.55-7.52 (m, 2 H), 7.30-7.26 (m, 2 H), 4.70 (s, 1 H), 3.93 (s, 3 H), 1.78 (s, 3 H); δ(cis) = 7.55-7.52 (m, 2 H), 7.30-7.26 (m, 2 H), 5.77 (s, 1 H), 3.94 (s, 3 H), 1.92 (s, 3 H); HRMS (ESI): m/z [M + H+] calcd for C11H12BrN2O: 267.0128; found: 267.0112. (1g) White solid; mp 86-87 ˚C; ¹H NMR (500 MHz, CDCl3): δ(trans) = 7.25-6.54 (m, 8 H), 4.51 (s, 1 H), 4.04 (s, 3 H), 4.00 (d, J = 14.5 Hz, 1 H), 3.87 (s, 3 H), 3.82 (s, 3 H), 3.19 (d, J = 15 Hz, 1 H); δ(cis) = 7.25-6.54 (m, 8 H), 5.54 (s, 1 H), 4.01 (s, 3 H), 3.85 (s, 3 H), 3.71 (s, 3 H), 3.58 (d, J = 6 Hz, 2 H); HRMS (ESI): m/z [M + H+] calcd for C19H21N2O3: 325.1547; found: 325.1555. (1h) White solid; mp 101-102 ˚C; ¹H NMR (500 MHz, CDCl3): δ(trans) = 7.52-6.76 (m, 8 H), 6.10 (s, 1 H), 4.11 (s, 3 H), 3.87 (s, 3 H), 3.84 (s, 3 H); δ(cis) = 7.52-6.76 (m, 8 H), 4.98 (s, 1 H), 3.95 (s, 3 H), 3.87 (s, 3 H), 3.80 (s, 3 H); HRMS (ESI): m/z [M + H+] calcd for C18H19N2O3: 311.1390; found: 311.1397. (1i) White solid: mp 80-81 ˚C; ¹H NMR (500 MHz, CDCl3): δ(trans) = 7.32-7.28 (m, 2 H), 6.93-6.90 (m, 2 H), 4.68 (s, 1 H), 3.93 (s, 3 H), 3.81 (s, 3 H), 1.77 (s, 3 H); δ(cis) = 7.32-7.28 (m, 2 H), 6.93-6.90 (m, 2 H), 5.75 (s, 1 H), 3.94 (s, 3 H), 3.81 (s, 3 H), 1.92 (s, 3 H). HRMS (ESI): m/z [M + H+] calcd for C12H15N2O2: 219.1128; found: 219.1135. (1j) White solid; mp 89-90 ˚C; ¹H NMR (500 MHz, CDCl3): δ(trans) = 6.59 (s, 2 H), 4.67 (s, 1 H), 3.96 (s, 3 H), 3.88 (s, 3 H), 3.85 (s, 3 H), 1.82 (s, 3 H); δ(cis) = 6.59 (s, 2 H), 5.77 (s, 1 H), 3.97 (s, 3 H), 3.87 (s, 3 H), 3.85 (s, 3 H), 1.94 (s, 3 H); HRMS (ESI): m/z [M + H+] calcd for C14H19N2O4: 279.1339; found: 279.1345. (1k) Colorless oil; ¹H NMR (400 MHz, CDCl3): δ(trans) = 7.31-7.29 (d, 2 H), 6.93-6.89 (m, 2 H), 4.68 (s, 1 H), 4.13 (t, J = 8.0 Hz, 2 H), 3.80 (s, 3 H), 1.78 (s, 3 H), 1.70-1.63 (m, 2 H), 1.44-1.26 (m 2 H), 0.95 (t, J = 9.0, 3 H); δ(cis) = 7.31-7.29 (d, 2 H), 6.93-6.89 (m, 2 H), 5.77 (s, 1 H), 4.13 (t, J = 8.0 Hz, 2 H), 3.80 (s, 3 H), 1.91 (s, 3 H), 1.70-1.63 (m, 2 H), 1.44-1.26 (m, 2 H), 0.95 (t, J = 9.0 Hz, 3 H); HRMS (ESI): m/z [M + H+] calcd for C15H21N2O2: 261.1598; found: 261.1610. (1n) White solid: mp 54-56 ˚C; ¹H NMR (500 MHz, CDCl3): δ(trans) = 7.38-7.34 (m, 5 H), 6.95-6.85 (m, 3 H), 5.11 (s, 2 H), 4.73 (s, 1 H), 3.89 (s, 3 H), 3.88 (s, 3 H), 1.81 (s, 3 H); δ(cis) = 7.38-7.34 (m 5 H), 6.95-6.85 (m, 3 H), 5.83 (s, 1 H), 5.10 (s, 2 H), 3.89 (s, 3 H), 3.87 (s, 3 H), 1.93 (s, 3 H); HRMS (ESI): m/z [M + H+] calcd for C19H21N2O3: 325.1547; found: 325.1553.

19

(dl-2a) White solid; mp 185-186 ˚C; ¹H NMR (400 MHz, CDCl3): δ = 7.36-7.33 (m, 1 H), 7.23 (d, J = 7.5 Hz, 2 H), 7.13 (d, J = 7.5 Hz, 2 H), 4.06 (s, 3 H), 1.91 (s, 3 H). ¹³C NMR (125 MHz, CDCl3): δ = 150.1, 131.8, 129.8, 129.7, 128.3, 118.0, 62.8, 59.8, 14.1; HRMS (ESI): m/z [M + Na+] calcd for C22H22N4NaO2: 397.1635; found: 397.1639. (dl-2b) White solid; mp 144-146 ˚C; ¹H NMR (500 MHz, CDCl3): δ = 7.06-7.00 (m, 4 H), 4.04 (s, 3 H), 2.33 (s, 3 H), 1.90 (s, 3 H); ¹³C NMR (125 MHz, CDCl3): δ = 150.4, 139.7, 129.8, 129.0, 128.8, 118.2, 62.7, 59.6, 21.3, 14.1; HRMS (ESI): m/z [M + Na+] calcd for C24H26N4NaO2: 425.1948; found: 425.1953. (dl-2c) White solid; mp 176-177 ˚C; ¹H NMR (500 MHz, CDCl3): δ = 7.05-7.01 (t, 4 H), 4.04 (s, 3 H), 2.54-2.48 (m, 1 H), 2.34 (s, 3 H), 1.83-1.74 (m, 2 H), 1.69-1.61 (m, 1 H), 0.88 (t, J = 7.0 Hz, 3 H); ¹³C NMR (125 MHz, CDCl3): δ = 153.4, 139.6, 130.0, 129.1, 128.9, 118.1, 62.6, 59.0, 31.9, 21.3, 19.6, 14.8; HRMS (ESI): m/z [M + Na+] calcd for C28H34N4NaO2: 481.2574; found: 481.2577. (dl-2d) White solid; mp 143-144 ˚C; ¹H NMR (500 MHz, CDCl3): δ = 7.27 (d, J = 11.5 Hz, 2 H), 7.09 (d, J = 11.5 Hz, 2 H), 4.05 (s, 3 H), 1.90 (s, 3 H); ¹³C NMR (125 MHz, CDCl3): δ = 149.8, 136.4, 131.2, 130.1, 128.7, 117.5, 62.9, 59.2, 14.1; HRMS (ESI): m/z [M + Na+] calcd for C22H20Cl2N4NaO2: 465.0856; found: 465.0861. (dl-2e) White solid; mp 160-161 ˚C; ¹H NMR (500 MHz, CDCl3): δ = 7.43 (d, J = 8.5 Hz, 2 H), 7.03 (d, J = 8.5Hz, 2 H), 4.05 (s, 3 H), 1.90 (s, 3 H); ¹³C NMR (125 MHz, CDCl3): δ = 149.7, 131.7, 131.4, 130.6, 124.7, 117.4, 62.9, 59.3, 14.1; HRMS (ESI): m/z [M + Na+] calcd for C22H20Br2N4NaO2: 552.9845; found: 552.9850. (dl-2f) White solid; mp 186-187 ˚C; ¹H NMR (500 MHz, CDCl3): δ = 6.77 (s, 2 H), 6.61 (s, 1 H), 4.05 (s, 3 H), 3.88 (s, 3 H), 3.67 (s, 3 H), 1.94 (s, 3 H); ¹³C NMR (125 MHz, CDCl3): δ = 150.2, 149.7, 148.1, 123.8, 122.3, 118.0, 112.8, 110.2, 62.5, 59.5, 55.9, 55.7, 13.9; HRMS (ESI): m/z [M + Na+] calcd for C26H30N4NaO6: 517.2058; found: 517.2065. (dl-2g) White solid; mp 189-190 ˚C; ¹H NMR (500 MHz, CDCl3): δ = 7.26 (d, J = 7.5 Hz, 2 H), 7.19-7.11 (m, 3 H), 6.70-6.60 (m, 3 H), 3.94 (s, 3 H), 3.93 (d, J = 14.0 Hz, 1 H), 3.85 (s, 3 H), 3.62 (s, 3 H), 3.47 (d, J = 14.5 Hz, 1 H); ¹³C NMR (125 MHz, CDCl3): δ = 151.6, 149.9, 148.1, 135.7, 129.6, 128.2, 126.5, 124.0, 122.8, 118.1, 113.2, 110.3, 62.7, 59.7, 56.1, 55.9, 35.2; HRMS (ESI): m/z [M + Na+] calcd for C38H38N4NaO6: 669.2684; found: 669.2689. (dl-2h) White solid; mp 198-199 ˚C; ¹H NMR (500 MHz, CDCl3): δ = 7.36-7.29 (m, 3 H), 6.84-6.82 (m, 5 H), 4.14 (s, 3 H), 3.90 (s, 3 H), 3.69 (s, 3 H); ¹³C NMR (125 MHz, CDCl3): δ = 152.0, 150.2, 148.2, 131.9, 129.8, 128.4, 128.3, 123.5, 118.0, 113.7, 110.5, 63.4, 61.4, 56.2, 55.9; HRMS (ESI): m/z [M + Na+] calcd for C36H34N4NaO6: 641.2371; found: 641.2377. (dl-2i) White solid; mp 146-147 ˚C; ¹H NMR (500 MHz, CDCl3): δ = 7.05 (d, J = 8.5 Hz, 2 H), 6.78 (d, J = 9.0 Hz, 2 H), 4.04 (s, 3 H), 3.80 (s, 3 H), 1.91 (s, 3 H); ¹³C NMR (125 MHz, CDCl3): δ = 160.5, 150.4, 131.2, 123.5, 118.3, 113.6, 62.7, 59.5, 55.5, 14.1; HRMS (ESI): m/z [M + Na+] calcd for C24H26N4NaO4: 457.1852; found: 457.1854. (dl-2j) White solid; mp 180-182 ˚C; ¹H NMR (500 MHz, CDCl3): δ = 6.42 (s, 1 H), 4.05 (s, 3 H), 3.84 (s, 3 H), 3.71 (s, 6 H), 1.97 (s, 3 H); ¹³C NMR (125 MHz, CDCl3): δ = 152.7, 150.2, 138.9, 127.1, 118.1, 107.1, 62.8, 61.1, 60.1, 56.3, 14.2; HRMS (ESI): m/z [M + Na+] calcd for C28H34N4NaO8: 577.2269; found: 577.2273. (dl-2k) White solid; mp 67-70 ˚C; ¹H NMR (500 MHz, CDCl3): δ = 7.04 (d, J = 8.0 Hz, 2 H), 6.77 (d, J = 9.0 Hz, 2 H), 4.27-4.19 (m, 2 H), 3.79 (s, 3 H), 1.91 (s, 3 H), 1.76 (quin, J = 7.0 Hz, 2 H), 1.45 (sext, J = 7.5 Hz, 2 H), 1.00 (t, J = 7.5 Hz, 3 H); ¹³C NMR (125 MHz, CDCl3): δ = 160.5, 149.9, 131.2, 123.8, 118.4, 113.6, 74.6, 59.6, 55.5, 31.8, 19.2, 14.2, 14.1; HRMS (ESI): m/z [M + Na+] calcd for C30H38N4NaO4: 541.2785; found: 541.2792. (dl-2l) White solid; mp 101-102 ˚C; ¹H NMR (500 MHz, CDCl3): δ = 9.18 (t, J = 8.0 Hz, 1 H), 6.89 (dd, J = 8.0, 2.5 Hz, 1 H), 6.80 (d, J = 7.5 Hz, 1 H), 6.65 (s, 1 H), 4.05 (s, 3 H), 3.64 (s, 3 H), 1.93 (s, 3 H); ¹³C NMR (125 MHz, CDCl3): δ = 159.3, 150.1, 133.3, 129.3, 121.9, 118.0, 115.9, 115.1, 62.8, 59.7, 55.4, 14.1; HRMS (ESI): m/z [M + Na+] calcd for C24H26N4NaO4: 457.1846; found: 457.1852. (dl-2l) White solid; mp 142-143 ˚C; ¹H NMR (500 MHz, CDCl3): δ = 7.33-7.30 (t, 1 H), 7.19-7.16 (t, 2 H), 7.05-6.99 (m, 4 H), 6.88 (d, J = 8.0 Hz, 1 H), 5.79 (d, J = 12 Hz), 5.10 (d, J = 12.5 Hz), 3.93 (s, 3 H), 3.89 (s, 3 H), 1.85 (s, 3 H); ¹³C NMR (125 MHz, CDCl3): δ = 150.8, 148.9, 131.3, 130.5, 129.6, 129.5, 128.0, 121.4, 117.9, 112.0, 111.0, 59.8, 56.0, 55.9, 14.3; HRMS (ESI): m/z [M + Na+] calcd for C38H38N4NaO6: 669.2684; found: 669.2689. (dl-2m) White solid; mp 163-164 ˚C; ¹H NMR (500 MHz, CDCl3): δ = 7.39 (d, J = 7.5 Hz, 1 H), 7.27 (d, J = 8.0 Hz, 1 H), 7.11 (d, J = 4.5 Hz, 1 H), 4.06 (s, 3 H), 1.93 (s, 3 H); ¹³C NMR (125 MHz, CDCl3): δ = 149.4, 134.7, 133.6, 130.3, 130.0, 129.7, 127.7, 117.2, 62.9, 59.4, 14.2; HRMS (ESI): m/z [M + Na+] calcd for C22H20Cl2N4NaO2: 465.0856; found: 465.0862. (dl-2n) White solid; mp 142-143 ˚C; ¹H NMR (500 MHz, CDCl3): δ = 7.33-7.30 (t, 1 H), 7.19-7.16 (t, 2 H), 7.05-6.99 (m, 4 H), 6.88 (d, J = 8.0 Hz, 1 H), 5.79 (d, J = 12 Hz), 5.10 (d, J = 12.5 Hz, 1 H), 3.93 (s, 3 H), 3.89 (s, 3 H), 1.85 (s, 3 H); ¹³C NMR (125 MHz, CDCl3): δ = 150.8, 148.9, 131.3, 130.5, 129.6, 129.5, 128.0, 121.4, 117.9, 112.0, 111.0, 76.7, 59.8, 56.0, 55.9, 14.3; HRMS (ESI): m/z [M + Na+] calcd for C38H38N4NaO6: 669.2684; found: 669.2689.

20

(dl-4) White solid; mp 202-204 ˚C; ¹H NMR (500 MHz, CDCl3): δ = 7.80 (d, J = 8.0 Hz, 1 H), 7.65 (d, J = 8.5 Hz, 1 H), 7.59-7.50 (m, 3 H), 7.44-7.41 (m, 1 H), 7.20-7.18 (t, 1 H), 4.14 (s, 3 H), 1.98 (s, 3 H); ¹³C NMR (125 MHz, CDCl3): δ = 150.3, 133.5, 132.5, 130.3, 129.1, 128.9, 128.0, 127.6, 127.6, 126.8, 126.3, 118.1, 62.9, 60.0, 14.3; HRMS (ESI): m/z [M + Na+] calcd for C30H26N4NaO2: 497.1948; found: 497.1949.(5) White solid; mp 100-101 ˚C; ¹H NMR (500 MHz, CDCl3): δ = 8.51 (d, J = 8.5 Hz, 1 H), 7.95 (d, J = 8.0 Hz, 1 H), 7.70-7.61 (m, 3 H), 7.54-7.50 (m, 1 H), 4.14 (s, 3 H), 2.70 (s, 3 H). This compound was well characterized in our previous report (see reference 11).

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(dl-9) White solid; mp 166-168 ˚C; ¹H NMR (500 MHz, CDCl3): δ = 7.06-6.99 (m, 8 H), 4.05 (s, 3 H), 4.03 (s, 3 H), 2.54-2.46 (m, 1 H), 2.34 (s, 6 H), 1.90 (s, 3 H), 1.84-1.78 (m, 1 H), 1.76-1.62 (m, 2 H), 0.88 (t, J = 7.5 Hz, 3 H); ¹³C NMR (125 MHz, CDCl3): δ = 153.4, 150.4, 139.7, 139.6, 130.0, 129.9, 129.8, 129.0, 128.9, 128.9, 128.8, 118.3, 118.0, 62.7, 62.6, 59.5, 59.1, 31.9, 21.3, 19.6, 19.5, 14.8, 14.1; HRMS (ESI): m/z [M + Na+] calcd for C26H30N4NaO2: 453.2261; found: 453.2268. (dl-10) White solid; mp 126-129 ˚C; ¹H NMR (500 MHz, CDCl3): δ = 7.35-7.31 (m, 2 H), 7.24-7.17 (m, 4 H), 7.07-7.03 (m, 5 H), 6.90 (d, J = 8.0 Hz, 1 H), 5.21 (q, 2 H), 3.93-3.92 (t, 9 H, 3 × OMe), 1.95 (s, 3 H), 1.78 (s, 3 H); ¹³C NMR (125 MHz, CDCl3):
δ = 151.1, 149.7, 149.1, 131.9, 131.5, 131.0, 129.8, 129.7, 129.6, 128.3, 128.2, 121.7, 118.1, 118.0, 112.4, 111.3, 77.0, 62.6, 59.9, 59.8, 56.2, 56.2, 14.6, 13.0; HRMS (ESI):
m/z [M + Na+] calcd for C30H30N4NaO4: 533.2159; found: 533.2165.(12) White solid; mp 161-162 ˚C; ¹H NMR (500 MHz, CDCl3): δ(dl) = 7.46-7.33 (m, 3 H), 7.03-7.01 (q, 2 H), 2.47 (s, 3 H); δ(meso) = 7.46-7.33 (m, 5 H), 2.31 (s, 3 H). For previous characterization of this compound, see reference 3. (dl-13) White solid; mp 139-141 ˚C; ¹H NMR (500 MHz, CDCl3): δ = 7.42-7.23 (m, 7 H), 7.10 (d, J = 7.5 Hz, 2 H), 6.70-6.96 (t, 4 H), 6.91 (d, J = 7.5 Hz, 1 H); ¹³C NMR (125 MHz, CDCl3): δ = 196.3, 151.4, 149.3, 149.2, 130.9, 130.3, 130.1, 129.9, 129.5, 129.4, 128.9, 128.5, 128.2, 120.9, 118.1, 117.3, 111.5, 111.2, 77.0, 64.4, 60.0, 56.2, 56.2, 28.4 (CH3), 14.5 (CH3); HRMS (ESI): m/z [M + Na+] calcd for C29H27N3NaO4: 504.1894; found: 504.1899.